Endocrine Abstracts

Intra-abdominal adiposity is associated with insulin resistance and increased cardiovascular morbidity and mortality. Consequently, there is a need to identify factors involved in adipose tissue distribution. Patients with glucocorticoid (GC) excess develop a classic phenotype characterized by central, but not peripheral, obesity. Differences in gene expression between omental (om) and subcutaneous (sc) adipose tissue have been described, however, the molecular mechanisms underpinning the differences in response to GCs have not been established. It is accepted that GCs cause global insulin resistance, however, we have previously shown that in differentiated sc pre-adipocytes GCs enhance insulin signalling and action. In this study we compare the regulation of insulin signalling by GCs in paired human om and sc isolated intact adipocytes. The expression and phosphorylation of key components of the insulin signalling cascade (IR, IRS1 and 2, akt 2) were measured using real-time PCR and western blotting following cortisol treatment (500 nM, 24 hr) and an insulin spike (50 nM, 15 min). Cortisol treatment increased mRNA expression of IRS2 in sc (AU, 0.22±0.07 [Ctrl], 0.62±0.21, P<0.05) but not om (AU, 0.46±0.09 [Ctrl], 0.64±0.17, P=ns) adipocytes. Expression of IR, IRS1 and akt 2 did not change in adipocytes from either depot. Cortisol increased insulin stimulated IR Tyr1158 phosphorylation in sc but not om adipocytes (sc: 1.68±0.02 fold, om: 0.73±0.14 fold). Consistent with increased IR activation insulin stimulated akt Ser473 phosphorylation was increased in cortisol treated sc adipocytes (1.58±0.2 fold P<0.05). Interestingly GC treatment failed to regulate PKB/akt phosphorylation in om adipocytes (0.97±0.2 fold P=ns). We have demonstrated adipose tissue depot specific regulation of insulin signalling by GCs. GCs enhanced insulin signalling in sc adipocytes, whilst failing to regulate insulin action in om cells. We have defined novel mechanisms, both transcriptional and post-translational, by which GCs differentially impact upon insulin action in sc and om depots. It is plausible that differential lipid flux, dependent upon the sc depot specific interaction between GCs and insulin, may underpin the adverse metabolic phenotype associated with GC excess.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.